Vhl deficiency in osteocytes produces high bone mass and hematopoietic defects

Bone. 2018 Nov:116:307-314. doi: 10.1016/j.bone.2018.08.022. Epub 2018 Aug 30.

Abstract

Tissue oxygen (O2) levels vary during development and disease; adaptations to decreased O2 (hypoxia) are mediated by hypoxia-inducible factor (HIF) transcription factors. HIFs are active in the skeleton, and stabilizing HIF-α isoforms cause high bone mass (HBM) phenotypes. A fundamental limitation of previous studies examining the obligate role for HIF-α isoforms in the skeleton involves the persistence of gene deletion as osteolineage cells differentiate into osteocytes. Because osteocytes orchestrate skeletal development and homeostasis, we evaluated the influence of Vhl or Hif1a disruption in osteocytes. Osteocytic Vhl deletion caused HBM phenotype, but Hif1a was dispensable in osteocytes. Vhl cKO mice revealed enhanced canonical Wnt signaling. B cell development was reduced while myelopoiesis increased in osteocytic Vhl cKO, revealing a novel influence of Vhl/HIF-α function in osteocytes on maintenance of bone microarchitecture via canonical Wnt signaling and effects on hematopoiesis.

Keywords: Hematopoiesis; Hypoxia-inducible factor; Osteocyte; Sclerostin; Wnt; von Hippel-Landau.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Bone and Bones / metabolism*
  • Cancellous Bone / pathology
  • Cortical Bone / pathology
  • Gene Deletion
  • Hematopoiesis*
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Lymphopoiesis
  • Mice, Inbred C57BL
  • Organ Size
  • Osteocytes / metabolism*
  • Von Hippel-Lindau Tumor Suppressor Protein / metabolism*
  • Wnt Signaling Pathway

Substances

  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Von Hippel-Lindau Tumor Suppressor Protein